Hepatotoxicity—

The trend in liver retention (not Illustrated) does not show the pronounced uptake for trans-[Pt(NH3)2Cl2] as in the kidney. Thus, the chemlcal-blogical processes leading to tissue retention (and perhaps organ toxicity) appear quite different for the liver V8 kidney. In this context, it is worthwhile to note that while uptake of cis-[Pt(NH3)2CI2] in the kidney can lead to nephrotoxicity, reports of hepatotoxicity associated with cis-[Pt(NH3)2CI2] chemotherapy are rare. 

ACS Symposium Series American Chemical Society Washington, DC, 1980. 

It is noteworthy that J s-[Pt(NH3)2Cl2] and K[Pt(NH3)Cl3), the two antitumor active complexes (% T/C 50), are also the two most mutagenic species as determined by the Ames and CHO/HGPRT test systems (27). The complexes are similar in that (a) through aquation the [Pt(NH3)Cl3] Ion can become a neutral molecule, cts-[Pt(NH3)(H20)Cl2] , and (b) both possess cis-reactive groups. Two Important criteria for antitumor activity to be exhibited are that complexes should be neutral and possess ois-reactlve groups. 

Toxicity. Acute toxicity and antitumor activity data for the chloroammineplatlnum(II) complexes is tabulated in Table VIII. 

FIGURE 10.2 Effects of alkylphenols on cell viability compared to the amounts of p-QMs formed in isolated rat hepatocytes. Source From Ref. 28, with permission from the American Chemical Society. 

In rat liver slices, evidence also supports the roles of QMs in mediating the toxicity of a series of 4-methylphenols.24 The potency correlates with rates of QM formation in the order 2-bromo-4-methylphenol 4-methylphenol = DMP TMP 2-methoxy-4-methylphenol. None of these compounds contain two bulky ortho substituents, so as discussed earlier the corresponding QMs are expected to be highly reactive. The authors suggested that differences in the reactivities of these QMs determine their relative toxic potencies as electron-donating substituents on the ring stabilize the QM and thereby reduce its toxicity (e.g., 2-methoxy-4-methylphenol is less toxic than DMP) and conversely, electron-withdrawing substituents destabilize QMs and enhance toxicity (e.g., 2-bromo-4-methylphenol is more potent than DMP). 

Other materials, such as bile acids and many xenobiotics, move from the hepatocytes into the bile-carrying canaliculi, which merge into larger ducts that follow the portal vein branches. The ducts merge into the hepatic duct from which bile drains into the upper part of the small intestine, the duodenum. The gall bladder serves to hold bile until it is emptied into the intestine. 

Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, North Carolina 27695 

College of Pharmacy, University of Louisiana at Monroe, Monroe, Louisiana 71209 

Paradoxically, the structures and functions of the liver predispose it to chemical toxicity. Hepatocytes are exposed to orally administered xenobiotics without systemic modification or dilution because they flow directly to the liver by the portal venous blood that delivers absorbed nutrients from the gastrointestinal tract. Xenobiotics may be extensively metabolized by the liver so that little of the parent xenobiotic enters the systemic circulation, a phenomenon known as the first pass effect. The movement of xenobiotics into the liver coupled with an opposing move- 

Molecular and Biochemical Toxicology, Fourth Edition, edited by Robert C. Smart and Ernest Hodgson Copyright 2008 John Wiley Sons, Inc. 

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Many other bisben2ylisoquinoliae alkaloids, such as tetrandriae (80), from Cjcleapeltata Hook., are also known. Compound (80), for example, although it causes hypotension and hepatotoxicity ia mammals, ia other tests, possessed enough anticancer activity to be considered for preclioical evaluation (55). The arrow poison tubocurare prepared from Chondrendendron spp. also contains the bisben2yhsoquiQoline alkaloid tubocurariae (9). 

Hydraziae is toxic and readily absorbed by oral, dermal, or inhalation routes of exposure. Contact with hydraziae irritates the skin, eyes, and respiratory tract. Liquid splashed iato the eyes may cause permanent damage to the cornea. At high doses it can cause convulsions, but even low doses may result ia ceatral aervous system depressioa. Death from acute exposure results from coavulsioas, respiratory arrest, and cardiovascular coUapse. Repeated exposure may affect the lungs, Hver, and kidneys. Of the hydraziae derivatives studied, 1,1-dimethylhydrazine (UDMH) appears to be the least hepatotoxic monomethyl-hydrazine (MMH) seems to be more toxic to the kidneys. Evidence is limited as to the effect of hydraziae oa reproductioa and/or development however, animal studies demonstrate that only doses that produce toxicity ia pregaant rats result ia embryotoxicity (164). 

Serious hepatotoxicity of tacrine has been documented. More recent data suggest, however, that this toxicity can be reduced by carehiUy monitoring semm alanine aminotransferase levels (125). The side effects of tacrine also include gastrointestinal disturbances and emesis, and alternative AChE therapies are being advanced. Velnacrine (20), a metaboUte of tacrine, was expected to have reduced hepatotoxicity. However, its limited efficacy and side-effect profile, which includes dmg-related hematological changes, caused it to be dropped from further development. 

Chronic use of these irreversible MAO inhibitors has been associated with life-threatening toxicity, ie, hepatotoxicity and hypertensive crisis. Interactions with tyramine contained in food and other drugs have severely limited use of irreversible MAO inhibitors. These MAO inhibitors are also nonselective, inhibiting both MAO-A and MAO-B isoenzymes. Furthermore, they interfere with the hepatic metabolism of many dmgs. 

Normally, dietary tyramine is broken down in the gastrointestinal tract by MAO and is not absorbed. In the presence of MAOI, however, all of its potent sympathomimetic actions are seen. Other side effects of MAOI include excessive CNS stimulation, orthostatic hypotension, weight gain, and in rare cases hepatotoxicity. Because the monoamine oxidase inhibitors exhibit greater toxicity, yet no greater therapeutic response than other, newer agents, clinical use has been markedly curtailed. The primary use for MAOIs is in the treatment of atypical depressions, eg, those associated with increased appetite, phobic anxiety, hypersomnolence, and fatigues, but not melancholia (2). 

Vinyhdene chloride is hepatotoxic, but does not appear to be a carcinogen (13—18). Pharmacokinetic studies indicate that the behavior of vinyl chloride and vinyhdene chloride in rats and mice is substantially different (19). No unusual health problems have been observed in workers exposed to vinyhdene chloride monomer over varying periods (20). Because vinyhdene chloride degrades rapidly in the atmosphere, air pollution is not likely to be a problem (21). Worker exposure is the main concern. Sampling techniques for monitoring worker exposure to vinyhdene chloride vapor are being developed (22). 

As regards toxicity, pyrazole itself induced hyperplasia of the thyroid, hepatomegaly, atrophy of the testis, anemia and bone marrow depression in rats and mice (72E1198). The 4-methyl derivative is well tolerated and may be more useful than pyrazole for pharmacological and metabolic studies of inhibition of ethanol metabolism. It has been shown (79MI40404) that administration of pyrazole or ethanol to rats had only moderate effects on the liver, but combined treatment resulted in severe hepatotoxic effects with liver necrosis. The fact that pyrazole strongly intensified the toxic effects of ethanol is due to inhibition of the enzymes involved in alcohol oxidation (Section 4.04.4.1.1). 

Yellow phosphorus was the first identified liver toxin. It causes accumulation of lipids in the liver. Several liver toxins such as chloroform, carbon tetrachloride, and bromobenzene have since been identified. I he forms of acute liver toxicity are accumulation of lipids in the liver, hepartxiellular necrosis, iii-trahepatic cholestasis, and a disease state that resembles viral hepatitis. The types of chrome hepatotoxicity are cirrhosis and liver cancer. 

Liver cancer can also be a consequence of exposure to hepatotoxic chemicals. Natural hepatocarcinogens include fungal aflatoxins. Synthetic hepato-carcinogens include nitrosoamines, certain chlorinated hydrocarbons, polychlorinated biphenyls (PCBs), chloroform, carbon tetrachloride, dimethyl-benzanthracene, and vinyl chloride.Table 5.15 lists the chemical compounds that induce liver cancer or cirrhosis in experimental animals or... 

A cinnamoylamide, cinromide (44), is a long-acting anticonvulsant similar in its clinical effects to phenacetamide but is less hepatotoxic. The synthesis involves the straightforward amidation of acid via the intermediate acid chloride (SOCl 2) It appears that the drug is mainly deethylated in... 

Strongly hepatotoxic cyclic heptapeptides produced by some species of freshwater cyanobacteria (blue-green algae) (28). These microcystins represent a health risk to humans through drinking water, since they have been found to act as tumor promoters (29). Several chromatographic analytical procedures for microcystins have been... 

Antiepileptics Na+, Ca2+ channels GABA receptors l Na+currents l Ca2+ currents GABA receptor activity l Excitability of peripheral and central neurons l Release of excitatory neurotransmitters Sedation, dizziness, cognitive impairment, ataxia, hepatotoxicity, thrombocytopenia... 

Two small molecule DTIs are argatroban (Novastan, MW 527 Da) and the oral thrombin inhibitor, ximelagatran (Exanta, MW 474 Da) Ximelagatran is an inactive pro-drug after absorption, it is metabolized to the active DTI, melagatran [MW 430 Da]. Concerns regarding hepatotoxicity have prevented (xi)melagatran... 

The effects of leukotrienes can be blocked at several levels. Inhibitors of FLAP or 5-LO inhibit LT synthesis at all levels. However, FLAP antagonists developed to date have been too hepatotoxic for human use. Zileuton, a 5-LO synthase inhibiting drug, also demonstrated some hepatotoxicity in a small percentage of patients, which was nonetheless entirely reversible. However, the short half-life of this compound requires four times daily... 

A number of quinolones had to be taken off the market due to toxic effects on the liver, heart, or other organs, that became recognized only after marketing (e.g. temafloxacin, trovafloxacin, grepafloxacin). A risk for severe cardiotoxicity, hepatotoxicity, or phototoxicity is... 

PYRAZINAMIDE Patients should have baseline liver functions tests to use as a comparison when monitoring liver function during pyrazinamide therapy. The nurse should monitor the patient closely for symptoms of a decline in hepatic functioning (ie, yellowing of the skin, malaise, liver tenderness, anorexia, or nausea). The primary health care provider may order periodic liver function tests. Hepatotoxicity appears to be dose related and may appear at any time during therapy. 

Acetaminophen may alter blood glucose test results, causing falsely lower blood glucose values. Use with the barbiturates, hydantoins, isoniazid, and rifampin may increase the toxic effects and possibly decrease the therapeutic effects of acetaminophen. The effects of the loop diuretics may be decreased when administered with acetaminophen. Hepatotoxicity has occurred in chronic alcoholics who are taking moderate doses of acetaminophen. 

When administering acetaminophen, the nurse assesses the overall health and alcohol usage of the patient before administration. fatients who are malnourished or abuse alcohol are at risk of developing hepatotoxicity (damage to the liver) with the use of acetaminophen. 

Tacrine is particularly damaging to the liver and can result in hepatotoxicity. Because tacrine is more likely to cause adverse reactions and drug interactions, it must be administered more frequently (4 times a day) and is rarely used in current therapy. Donepezil has fewer and milder side effects than tacrine It is considered the agent of first choice However, some patients may achieve a better response with one drug than another. Additional adverse reactions are listed in the Summary Drug Table Cholinesterase Inhibitors. 

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